肿瘤内和外周血上的血管和PD-1作为结节性淋巴细胞中主要霍奇金淋巴瘤中的免疫生物标志物
Intra-tumoral and peripheral blood TIGIT and PD-1 as immune biomarkers in nodular lymphocyte predominant Hodgkin lymphoma
影响因子:9.90000
分区:医学1区 Top / 血液学2区
发表日期:2024 Nov
作者:
Jay Gunawardana, Soi C Law, Muhammed B Sabdia, Éanna Fennell, Aoife Hennessy, Ciara I Leahy, Paul G Murray, Karolina Bednarska, Sandra Brosda, Judith Trotman, Leanne Berkahn, Andreea Zaharia, Simone Birch, Melinda Burgess, Dipti Talaulikar, Justina N Lee, Emily Jude, Eliza A Hawkes, Sanjiv Jain, Karthik Nath, Cameron Snell, Fiona Swain, Joshua W D Tobin, Colm Keane, Mohamed Shanavas, Emily Blyth, Christian Steidl, Kerry Savage, Pedro Farinha, Merrill Boyle, Barbara Meissner, Michael R Green, Francisco Vega, Maher K Gandhi
摘要
在经典的霍奇金淋巴瘤（CHL）中，对免疫检查封锁（ICB）的反应与特定的肿瘤微环境（TME）和外周血特征有关。 ICB在结节性淋巴细胞中的作用尚未确定霍奇金淋巴瘤（NLPHL）。为了洞悉其在NLPHL中的潜力，我们使用综合多媒体分析比较了HLS之间的TME和外周血信号。 121个NLPHL和114例CHL患者的发现/验证方法突出显示了编程细胞死亡-1（PD-1）和T-Cell Ig和ITIM域（Tigit）基因表达中NLPHL与CHL的富集。多重成像显示与CHL相比，NLPHL中PD-1（和/或Tigit）CD4 T细胞和PD-1 CD8 T细胞的肿瘤内蛋白表达明显增加。这包括用淋巴细胞占主导地位（LP）和霍奇金芦苇（HRS）细胞玫瑰花的T细胞。在NLPHL中，肿瘤内PD-1 CD4 T细胞经常表达TCF-1，这是T-Cell对ICB反应增强的标志物。 HLS之间的外周血特征也不同，在NLPHL与CHL中，Th1，Th2和调节性CD4 T细胞中的PD-1 Tigit水平较高。循环PD-1 CD4具有高水平的TCF-1。值得注意的是，在两种淋巴瘤中，TME也存在着血液中高度扩张的克隆Tigit PD-1 CD4和Tigit PD-1 CD8 T细胞的种群，这表明表达T-Cell的T细胞在肿瘤内和血液腔室之间循环。在体外测定中，ICB能够减少LP和HRS细胞周围的玫瑰花结构的形成，这表明玫瑰花结的破坏可能是ICB在HL中的作用机理。总体而言，结果表明在NLPHL中保证对ICB的进一步评估。
Abstract
In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.